Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.

Bat wings are important for thermoregulation, but their role in heat balance during flight is largely unknown. More than 80% of the energy consumed during flight generates heat as a by-product, and thus it is expected that bat wings should dissipate large amounts of heat to prevent hyperthermia. We measured rectal (T(r)) and surface (T(s)) temperatures of Brazilian free-tailed bats (Tadarida brasiliensis) as they emerged from and returned to their daytime roosts and calculated sensible heat transfer for different body regions (head, body, wings, and tail membrane). Bats' T(r) decreased from 36.8°C during emergence flights to 34.4°C during returns, and T(s) scaled positively with ambient temperature (T(a)). Total radiative heat loss from bats was significantly greater for a radiative sink to the night sky than for a sink with temperature equal to T(a). We found that free-ranging Brazilian free-tailed bats, on average, do not dissipate heat from their wings by convection but instead dissipate radiative heat (L) to the cloudless night sky during flight ([Formula: see text] W). However, within the range of T(a) measured in this study, T. brasiliensis experienced net heat loss between evening emergence and return flights. Regional hypothermia reduces heat loss from wings that are exposed to potentially high convective fluxes. Additional research is needed to establish the role of wings in evaporative cooling during flight in bats.

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